The lymphatic vasculature plays a critical role in the pathogenesis of many diseases including inflammatory disorders, lymphedema, tumor progression, and metastasis. More recently, the important role of lymphatic vessels in disease states such as tumor dissemination and metastasis has been recognized with the correlation of the number of tumor-associated lymphatic vessels with lymph node metastasis. Discovery and characterization of the lymphatic vessel microenvironment in terms of protein expression levels and their regulatory function will help unravel the specific role lymphatic vessels play in these disease states among others (lymphedema, lymphangioma, tissue repair, inflammation, and psoriatic skin lesions). We have extensive experience with the in vivo selection system in which peptides that home selectively to different tissues are recovered after intravenous administration of a bacteriophage (phage) random peptide library. Here we propose to adapt this selection process and perform an ex vivo phage screening on lymphatic vessels removed during sentinel lymphatic mapping and lymph node biopsy procedures. We may additionally employ several phage display-based approaches to define the cellular and molecular differences that exist in lymphatic channels. These screenings will unveil lymphatic targeting peptides, which will ultimately lead to receptor identification and provide a more complete molecular profile of the lymphatic endothelium and a basis for ligand-directed imaging. We also anticipate that the targeted ligands identified here may be useful in the development of new strategies in the understanding/prevention of metastasis and targeted imaging to monitor the progression of diseases, such as lymphedema. Our Specific Aims are: (i) To isolate lymphatic vessel homing peptides and identify the corresponding lymphatic cell surface receptors and (ii) To evaluate the lymphatic receptor homing capabilities for the design of targeted molecular imaging. We hypothesize that molecular addresses among lymphatic vessels can be exploited for ligand-based imaging of functional and/or diseased lymphatic vessels.